Abstract Peripheral artery disease (PAD) affects 8.5 million of Americans over 40 years of age. Recent evidence from out work and others suggest the central role of oxidative stress in the pathophysiology of PAD and its association with greater walking impairment and decline in quality of life. Few therapeutic treatments can improve walking distances and quality of life in PAD patients. A new emerging therapeutic approach for PAD is the usage of mircroRNAs (miRs). miRs are endogenous 21?25 nucleotides noncoding RNA, that can regulate posttranscriptional gene expression. The most common mechanism of action of miRs is by binding to the 3' un- translated region of a target mRNA and thereby reducing mRNA expression or protein translation. Circulating miRNAs, represent potential biomarkers for the diagnosis and prognosis of PAD and a starting point for individualized treatment. Recent evidence in PAD and hindlimb ischemia models have identified miR-210 as a master regulator of gene expression under hypoxic conditions. Preliminary work from our laboratory has demonstrated that miR-210 in the serum and gastrocnemius samples is increased and positively correlated with disease progression. Furthermore, we have identified that revascularization operations can decrease circulating miR-210 in the serum of PAD patients six-months after the operation. It has been shown that miR-210 can negatively regulate mitochondrial respiratory activity and increase reactive species generation by inhibiting the ISCU (iron-sulfur cluster scaffold homolog) and COX10 (cytochrome c oxidase assembly protein). Thus, our central hypothesis, is that miR-210 gene expression is a master regulator of oxidative stress and is associated with mitochondrial dysfunction, oxidative metabolism, walking function and quality of life. Aim #1: miR-210 gene expression in the gastrocnemius and serum of patients with PAD, is different than healthy age matched controls, and correlates with oxidative stress, oxidative metabolism, mitochondrial function, walking function and quality of life. Aim #2: Endovascular and open bypass revascularization procedures can regulate oxidative stress by decreasing miR-210 expression in the gastrocnemius and serum of PAD patients and improve mitochondrial function, oxidative metabolism, walking function and quality of life. Aim #3: Utilize in-vitro studies in a novel normoxia/hypoxia/hyperoxia model of PAD to determine the extent to which gene expression changes by inducing/inhibiting miR-210 gene expression and its interactions with mRNA expression.